Co-assembled whey protein and proanthocyanidins as a promising biocarrier for hydrophobic pterostilbene: Fabrication, characterization, and cellular antioxidant potential.

The usage of food-derived polyphenols with different polarities has been limited by their instability and incompatibility. Therefore, a biocarrier was developed by co-assembly of whey protein isolate (WPI) and hydrophilic proanthocyanidin (PC) for loading hydrophobic pterostilbene (PTE). Such biocarrier has superior affinity for PTE than WPI alone, as determined by encapsulation efficiency and loading capacity assay, fluorescence quenching analysis, and molecular docking, whereas the assembly process was characterized by particle size and zeta potential, 3-dimensional fluorescence, and scanning electron microscopy. Circular dichroism and Fourier transform infrared spectroscopy spectra confirmed the α-helix to ß-sheet and random coil transition of proteins during the formation of nanocomplexes. Whey protein isolate acted as a mediator through altering the binding mode of PC and PTE, allowing them to perform significant synergistic effects in enhancing 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) and 2,2-diphenyl-1-picrylhydrazyl radical scavenging and reducing H2O2-induced cell damage. This research may serve to develop new protein/polyphenol co-loading systems and offer a reliable nutritional fortification.

Transmucosal Delivery of Nasal Nanovaccines Enhancing Mucosal and Systemic Immunity.

Intranasal vaccines can induce protective immune responses at the mucosa surface entrance, preventing the invasion of respiratory pathogens. However, the nasal barrier remains a major challenge in the development of intranasal vaccines. Herein, a transmucosal nanovaccine based on cationic fluorocarbon modified chitosan (FCS) is developed to induce mucosal immunity. In our system, FCS can self-assemble with the model antigen ovalbumin and TLR9 agonist CpG, effectively promoting the maturation and cross-presentation of dendritic cells. More importantly, it can enhance the production of secretory immunoglobin A (sIgA) at mucosal surfaces for those intranasally vaccinated mice, which in the meantime showed effective production of immunoglobulin G (IgG) systemically. As a proof-of-concept study, such a mucosal vaccine inhibits ovalbumin-expressing B16-OVA melanoma, especially its lung metastases. Our work presents a unique intranasal delivery system to deliver antigen across mucosal epithelia and promote mucosal and systemic immunity.

Surface-enhanced Raman scattering spectroscopy monitoring and degradation of organic pollutants using a novel nanowire.

A multifunctional Ag/AlOOH nanowires (ANW) composite substrate was constructed, which not only accomplishes highly sensitive detection of organic dye molecules, but also has excellent performance in the degradation of pollutants. The ANW in the Ag/ANW substrate possesses a high aspect ratio, which extends the distribution area of Ag and enables a large number of hot spots on the active substrate. Additionally, due to the abundant OH groups on the ANW, there is an increased number of anchor sites for adsorbed metal ions in the Ag/ANW compound, thus contributing to the enhancement and degradation of molecules. Moreover, the constructed multifunctional Ag/ANW nanocomplexes also show great promise for practical applications, providing a reference for the detection and degradation of contaminants.

Self-assembled pea vicilin nanoparticles as nanocarriers for improving the antioxidant activity, environmental stability and sustained-release property of curcumin.

BACKGROUND: The application of curcumin (Cur) in the food industry is usually limited by its low water solubility and poor stability. This study aimed to fabricate self-assembled nanoparticles using pea vicilin (7S) through a pH-shifting method (pH 7-pH 12-pH 7) to develop water-soluble nanocarriers of Cur. RESULTS: Intrinsic fluorescence, far-UV circular dichroism spectra and transmission electron microscopy analysis demonstrated that the structure of 7S could be unfolded at pH 12.0 and refolded when the pH shifted to 7.0. The assembled 7S-Cur exhibited a high loading ability of 81.63 µg mg-1 for Cur and homogeneous particle distribution. Cur was encapsulated in the 7S hydrophobic nucleus in an amorphous form and combined through hydrophobic interactions and hydrogen bonding, resulting in the static fluorescence quenching of 7S. Compared with free Cur, the retention rates of Cur in 7S-Cur were approximately 1.12 and 1.70 times higher under UV exposure at 365 nm or heating at 75 °C for 120 min, respectively, as well as 7S-Cur showing approximately 1.50 times higher antioxidant activity. During simulated gastrointestinal experiments, 7S-Cur exhibited a better sustained-release property than free Cur. CONCLUSION: The self-assembled 7S nanocarriers prepared using a pH-shifting method effectively improved the antioxidant activity, environmental stability and sustained-release property of Cur. Therefore, 7S isolated from pea protein could be used as potential nanocarriers for Cur. © 2023 Society of Chemical Industry.

Coordinated modulation of long non-coding RNA ASBEL and curcumin co-delivery through multicomponent nanocomplexes for synchronous triple-negative breast cancer theranostics.

BACKGROUND: Abnormally regulated long non-coding RNAs (lncRNAs) functions in cancer emphasize their potential to serve as potential targets for cancer therapeutic intervention. LncRNA ASBEL has been identified as oncogene and an anti-sense transcript of tumor-suppressor gene of BTG3 in triple-negative breast cancer (TNBC). RESULTS: Herein, multicomponent self-assembled polyelectrolyte nanocomplexes (CANPs) based on the polyelectrolytes of bioactive hyaluronic acid (HA) and chitosan hydrochloride (CS) were designed and prepared for the collaborative modulation of oncogenic lncRNA ASBEL with antago3, an oligonucleotide antagonist targeting lncRNA ASBEL and hydrophobic curcumin (Cur) co-delivery for synergetic TNBC therapy. Antago3 and Cur co-incorporated CANPs were achieved via a one-step assembling strategy with the cooperation of noncovalent electrostatic interactions, hydrogen-bonding, and hydrophobic interactions. Moreover, the multicomponent assembled CANPs were ulteriorly decorated with a near-infrared fluorescence (NIRF) Cy-5.5 dye (FCANPs) for synchronous NIRF imaging and therapy monitoring performance. Resultantly, MDA-MB-231 cells proliferation, migration, and invasion were efficiently inhibited, and the highest apoptosis ratio was induced by FCANPs with coordination patterns. At the molecular level, effective regulation of lncRNA ASBEL/BTG3 and synchronous regulation of Bcl-2 and c-Met pathways could be observed. CONCLUSION: As expected, systemic administration of FCANPs resulted in targeted and preferential accumulation of near-infrared fluorescence signal and Cur in the tumor tissue. More attractively, systemic FCANPs-mediated collaborative modulating lncRNA ASBEL/BTG3 and Cur co-delivery significantly suppressed the MDA-MB-231 xenograft tumor growth, inhibited metastasis and extended survival rate with negligible systemic toxicity. Our present study represented an effective approach to developing a promising theranostic platform for combating TNBC in a combined therapy pattern.

Development of Novel Nano-Sized Imine Complexes Using Coriandrum sativum Extract: Structural Elucidation, Non-Isothermal Kinetic Study, Theoretical Investigation and Pharmaceutical Applications.

A new Schiff base (H2L) generated from sulfamethazine (SMT), as well as its novel micro- and nanocomplexes with Ni(II) and Cd(II) metal ions, have been synthesized. The proposed structures of all isolated solid compounds were identified with physicochemical, spectral, and thermal techniques. Molar conductance studies confirmed that the metal complexes are not electrolytic. The molecular geometry located at the central metal ion was found to be square planar for the NiL2 and tetrahedral for the CdL2 complexes. The kinetic and thermal parameters were obtained using the Coats and Redfern approach. Coriandrum sativum (CS) in ethanol was used to create the eco-friendly Ni and Cd nanocomplexes. The size of the obtained nanoparticles was examined using PXRD and TEM, and found to be in the sub-nano range (3.07-4.61 nm). Furthermore, the TEM micrograph demonstrated a uniform and homogeneous surface morphology. The chemistry of the prepared nanocomplexes was studied using TGA and TEM techniques. The effect of temperature on the prepared nanocomplexes' size revealed a decrease in size by heating. Furthermore, the nanocomplexes' antimicrobial and anticancer properties were evaluated. The outcomes demonstrated that the nanocomplexes exhibited better antimicrobial properties. Moreover, the antitumor results showed that after heating, the Ni nanocomplex exhibited a substantial antitumor activity (IC50 = 1.280 g/mL), which was higher than the activity of cis-platin (IC50 = 1.714 g/mL). Finally, molecular-docking studies were performed to understand the evaluated compounds' ability to bind to methionine adenosyl-transferases (PDB ID: 5A19) in liver cancer and COVID-19 main protease (PDB ID: 6lu7) cell-proteins. The findings reveal that [NiL2]·1.5H2O2 has a higher binding energy of -37.5 kcal/mol with (PDB ID: 5A19) cell protein.

Fabrication of glycated yeast cell protein via Maillard reaction for delivery of curcumin: improved environmental stability, antioxidant activity, and bioaccessibility.

BACKGROUND: The application of curcumin (CUR) in the food industry is limited by its instability, hydrophobicity and low bioavailability. Yeast cell protein (YCP) is a by-product of spent brewer's yeast, which has the potential to deliver bioactive substances. However, the environmental stresses such as pH, salt and heat treatment has restricted its application in the food industry. Maillard reaction as a non-enzymatic browning reaction can improve protein stability under environmental stress. RESULTS: The CUR was successfully encapsulated into the hydrophobic core of YCP/glycated YCP (GYCP) and enhanced by hydrogen bonding, resulting in static fluorescence quenching of YCP/GYCP. The average diameter and dispersibility of GYPC-CUR nanocomplex were significantly improved after glucose glycation (121.40 nm versus 139.70 nm). Moreover, the encapsulation capacity of CUR was not influenced by glucose glycation. The oxidative stability and bioaccessibility of CUR in nanocomplexes were increased compared with free CUR, especially complexed with GYCP conjugates. CONCLUSION: Steric hindrance provided by glucose conjugation improved the enviriomental stability, oxidative activity and bioaccessibility of CUR in nanocomplexes. Thus, glucose-glycated YCP has potential application as a delivery carrier for hydrophobic compounds in functional foods. © 2022 Society of Chemical Industry.

Influence of environmental pH on the interaction properties of WP-EGCG non-covalent nanocomplexes.

BACKGROUND: Whey protein-epigallocatechin gallate (WP-EGCG) covalent conjugates and non-covalent nanocomplexes were prepared and compared using Fourier-transform infrared spectra. The effect of pH (at 2.6, 6.2, 7.1, and 8.2) on the non-covalent nanocomplexes' functional properties and the WP-EGCG interactions were investigated by studying antioxidant activity, emulsification, fluorescence quenching, and molecular docking, respectively. RESULTS: With the formation of non-covalent and covalent complexes, the amide band decreased; the -OH peak disappeared; the antioxidant activity of WP-EGCG non-covalent complexes was 2.59- and 2.61-times stronger than WP-EGCG covalent conjugates for 1-diphenyl-2-picryl-hydrazyl (DPPH) and ferric reducing ability of plasma (FRAP), respectively (particle size: 137 versus 370 nm). The antioxidant activity (DPPH 27.48-44.32%, FRAP 0.47-0.63) was stronger at pH 6.2-7.1 than at pH 2.6 and pH 8.2 (DPPH 19.50% and 26.36%, FRAP 0.39 and 0.41). Emulsification was highest (emulsifying activity index 181 m2 g-1 , emulsifying stability index 107%) at pH 7.1. The interaction between whey protein (WP) and EGCG was stronger under neutral and weakly acidic conditions: KSV (5.11-8.95 × 102 L mol-1 ) and Kq (5.11-8.95 × 1010 L mol s-1 ) at pH 6.2-7.1. Binding constants (pH 6.2 and pH 7.1) increased with increasing temperature. Molecular docking suggested that hydrophobic interactions played key roles at pH 6.2 and pH 7.1 (∆H > 0, ∆S > 0). Hydrogen bonding was the dominant force at pH 2.6 and pH 8.2 (∆H < 0, ∆S < 0). CONCLUSION: Environmental pH impacted the binding forces of WP-EGCG nanocomplexes. The interaction between WP and EGCG was stronger under neutral and weakly acidic conditions. Neutral and weakly acidic conditions are preferable for WP-EGCG non-covalent nanocomplex formation. © 2023 Society of Chemical Industry.

TfR Aptamer Enhanced Blood-Brain Barrier Penetration of Biomimetic Nanocomplexes for Intracellular Transglutaminase 2 Imaging and Silencing in Glioma.

Engineering a versatile nanocomplex integrating effective penetration of the blood-brain barrier (BBB), accurate diagnosis, and boosting therapy has always been an intractable challenge in glioblastoma multiforme (GBM). Herein, biomimetic nanocomplexes (TMPsM) for single intracellular transglutaminase 2 (TG2)-triggered self-assembly imaging and RNAi therapy for GBM are subtly developed. To prove the concept, transferrin receptor (TfR) aptamer-modified brain metastatic tumor cell membrane is prepared as the shell for dual BBB targeting capability and prolonged blood retention time. Upon targeting entering into GBM, hollow MnO2 is decomposed to release KKGKGQQ-tetraphenylethene (Pep-TPE) and siRNA. Owing to TG2 dependence, the non-emissive Pep-TPE would be self-aggregated to induce the emission turn-on in GBM that contain overexpressed TG2. The resulting aggregation-induced emission fluorescence imaging with a high signal-to-noise ratio can achieve the precise localization of the tumor and dynamic detection of TG2 activity, thereby allowing the GBM accurate diagnosis. Notably, the TG2 can be silenced by the released siRNA to cause cell apoptosis and increase chemotherapeutic sensitivity, ultimately realizing excellent antitumor efficacy. In vitro and in vivo results demonstrate that the as-prepared TMPsM indeed possess superior BBB penetration, precise diagnosis, and effective therapy of GBM. The proposed strategy may pioneer a new path for the theranostics of brain tumors.

Co-Delivery of Doxorubicin and Anti-PD-L1 Peptide in Lipid/PLGA Nanocomplexes for the Chemo-Immunotherapy of Cancer.

The combined delivery of chemotherapeutics with checkpoint inhibitors of the PD-1/PD-L1 pathway provides a new approach for cancer treatment. Small-molecule peptide inhibitors possess short production cycle, low immunogenicity, and fewer side effects; however, their potential in cancer therapy is hampered by the rapid biodegradation and a nanocarrier is needed for efficient drug delivery. Herein, anticancer drug doxorubicin (DOX) and PD-L1 inhibitor peptide P-12 are co-loaded by a lipid polymer nanocomplex based on poly(lactic-co-glycolic acid) (PLGA) and DSPE-PEG. Octaarginine (R8)-conjugated DSPE-PEG renders the LPN efficient internalization by cancer cells. The optimal nanomedicine LPN-30-R82K@DP shows a diameter of 125 nm and a DOX and P-12 loading content of 5.0 and 6.2%, respectively. LPN-30-R82K@DP exhibits good physiological stability and enhanced cellular uptake by cancer cells. It successfully induces immunogenic cell death and PD-L1 blockade in CT26 cancer cells. The in vivo antitumor study further suggests that co-loaded nanomedicine efficiently suppresses CT26 tumor growth and elicits antitumor immune response. This study manifests that lipid polymer nanocomplexes are promising drug carriers for the efficient chemo-immunotherapy of cancer.

Combinatorial cetuximab targeted polymeric nanocomplexes reduce PRC1 level and abrogate growth of metastatic hepatocellular carcinoma in vivo with efficient radionuclide uptake.

Hepatocellular carcinoma (HCC) is the most aggressive form of cancer with poor drug responses. Developing an effective drug treatment remains a major unmet clinical need for HCC. We report a comprehensive study of combinatorial Cetuximab (Cet) targeted polymeric poly(D, L-lactide-co-glycolide)-b-poly(ethylene glycol) nanocomplexes delivery of Combretastatin A4 (CA4) and 2-Methoxyestradiol (2ME) (Cet-PLGA-b-PEG-CA4 NP + Cet-PLGA-b-PEG-2ME NP) against metastatic HCC in SCID mice. 125I-Cet-PLGA-b-PEG NP showed potent accumulation and retention in HCC tumors with longer circulation time up to 48 h (18 ±â€¯1.0% ID/g, P < .0001). Combinatorial treatment with targeted polymeric nanocomplexes presented significant tumor growth inhibition (85%, P < .0001) than the free drug combinatorial counterpart, effectively inhibited orthotopic HCC and prevented lung metastasis. Combinatorial nanocomplexes treatment significantly blocked PRC1, a novel target of therapeutic response against HCC. Thus, the combinatorial cetuximab-targeted polymeric nanocomplexes possess superior antitumor activity against metastatic HCC and provide supports for the clinical translation ahead.

Synthesis and In Vitro Testing of YVO4:Eu3+@silica-NH-GDA-IgG Bio-Nano Complexes for Labelling MCF-7 Breast Cancer Cells.

We present a visual tool and facile method to detect MCF-7 breast cancer cells by using YVO4:Eu3+@silica-NH-GDA-IgG bio-nanocomplexes. To obtain these complexes, YVO4:Eu3+ nanoparticles with a uniform size of 10-25 nm have been prepared firstly by the hydrothermal process, followed by surface functionalization to be bio-compatible and conjugated with cancer cells. The YVO4:Eu3+@silica-NH-GDA-IgG nanoparticles exhibited an enhanced red emission at 618 nm under an excitation wavelength of 355 nm and were strongly coupled with MCF-7 breast cancer cells via biological conjugation. These bio-nanocomplexes showed a superior sensitiveness for MCF-7 cancer cell labelling with a detection percentage as high as 82%, while no HEK-293A healthy cells were probed under the same conditions of in vitro experiments. In addition, the detection percentage of MCF-7 breast cancer cells increased significantly via the functionalization and conjugation of YVO4:Eu3+ nanoparticles. The experimental results demonstrated that the YVO4:Eu3+@silica-NH-GDA-IgG bio-nanocomplexes can be used as a promising labelling agent for biomedical imaging and diagnostics.

Curcumin-Induced Stabilization of Protein-Based Nano-Delivery Vehicles Reduces Disruption of Zwitterionic Giant Unilamellar Vesicles.

Curcumin-loaded native and succinylated pea protein nanoparticles, as well as zwitterionic giant unilamellar vesicles were used in this study as model bioactive compound loaded-nanoparticles and biomembranes, respectively, to assess bio-nano interactions. Curcumin-loaded native protein-chitosan and succinylated protein-chitosan complexes, as well as native protein-chitosan and succinylated protein-chitosan hollow, induced leakage of the calcein encapsulated in the giant unilamellar vesicles. The leakage was more pronounced with hollow protein-chitosan complexes. However, curcumin-loaded native protein and curcumin-loaded succinylated protein nanoparticles induced calcein fluorescence quenching. Dynamic light scattering measurements showed that the interaction of curcumin-loaded native protein, curcumin-loaded succinylated protein, native protein-chitosan, and succinylated protein-chitosan complexes with the giant unilamellar vesicles caused a major reduction in the size of the lipid vesicles. Confocal and widefield fluorescence microscopy showed rupturing of the unilamellar vesicles after treatment with native pea protein-chitosan and succinylated pea protein-chitosan complexes. The nature of interaction between the curcumin-loaded protein nanoparticles and the biomembranes, at the bio-nano interface, is influenced by the encapsulated curcumin. Findings from this study showed that, as the protein plays a crucial role in stabilizing the bioactive compound from chemical and photodegradation, the encapsulated nutraceutical stabilizes the protein nanoparticle to reduce its interaction with biomembranes.

Characteristics and structure of a soy protein isolate-lutein nanocomplex produced via high-pressure homogenization.

BACKGROUND: In recent years, nanocarriers for transporting active substances have attracted attention. This study was to explore the soy protein isolate (SPI) after high-pressure homogenization (HPH) (0, 30, 60, 90 and 120 MPa) as potential lutein carriers. RESULTS: The load amount (LA) and encapsulation efficiency (EE) of the SPI-lutein nanocomplexes at a homogenization pressure of 60 MPa were the highest (2.32 mg mL-1 and 92.85%, respectively), and the average particle size and ζ-potential of the SPI-lutein nanocomplexes were 192.1 nm and -30.06 mV, respectively. The DPPH (2,2-diphenyl-1-picrylhydrazyl) and hydroxyl-antioxidant activities of the complex increased from 12.4% and 23.3% to 52.7% and 61.07%, respectively, after the protein was treated with HPH. The surface hydrophobicity of the SPI and the SPI-lutein nanocomplexes increased with increasing homogenization pressure treatment. Fourier transform-infrared spectrophotometry analyses suggested that the homogenization treatments resulted in partial unfolding of the protein molecules, and the addition of lutein can also lead to the change of protein secondary structure. The fluorescence emission of SPI was quenched by lutein through the static quenching mechanism. Fluorescence experiments revealed that SPI and lutein had the strongest binding ability through hydrophobic interaction at a homogenization pressure of 60 MPa. CONCLUSION: After HPH, the combination of SPI and lutein was beneficial, and the stability of lutein also improved after the combination. This study is conducive to expanding the application of soybean protein in the food industry. © 2022 Society of Chemical Industry.

Formulation of Glycyrrhizic Acid-based Nanocomplexes for Enhanced Anti-cancer and Anti-inflammatory Effects of Curcumin.

In this study, nanocomplexes composed of glycyrrhizic acid (GA) derived from the root of the licorice plant (Glycyrrhiza glabra) were formulated for the delivery of curcumin (CUR). Sonication of amphiphilic GA solution with hydrophobic CUR resulted in the production of nanosized complexes with a size of 164.8 ± 51.7 nm, which greatly enhanced the solubility of CUR in aqueous solution. A majority of the CURs were released from these GA/ CUR nanocomplexes within 12 h. GA/CUR nanocomplexes exhibited excellent intracellular uptake in human breast cancer cells (Michigan cancer foundation-7/multi-drug resistant cells), indicating enhanced anti-cancer effects compared to that of free CUR. In addition, GA/CUR nanocomplexes demonstrated high intracellular uptake into macrophages (RAW264.7 cells), consequently reducing the release of the pro-inflammatory cytokine tumor necrosis factor-α. Furthermore, GA/CUR nanocomplexes successfully reduced the levels of serum pro-inflammatory cytokines and splenomegaly in a rheumatoid arthritis model.

ciRS-7 is a prognostic biomarker and potential gene therapy target for renal cell carcinoma.

Circular RNAs are a new class of non-coding RNAs that have been shown to play critical roles in the development and progression of renal cell carcinoma (RCC). However, little is known about the functional mechanisms and therapeutic role of ciRS-7 in RCC. A series of in vitro and in vivo experiments were performed to investigate the functional mechanism and therapeutic role of ciRS-7, such as real-time quantitative PCR, CCK-8, wound healing, transwell, colony formation, Edu, tumor xenograft and lung metastasis in NSG mice. RNA pull-down, dual luciferase reporter, fluorescence in situ hybridization (FISH) and rescue assays were used to determine the relationship between ciRS-7, miR-139-3p and TAGLN. In addition, we constructed PBAE/si-ciRS-7 nanocomplexes with PBAE material to evaluate the therapeutic effect of the nanocomplexes on tumor in vivo. ciRS-7 was highly expressed in RCC tumor tissues and cell lines, and high ciRS-7 expression correlated with tumor size, high Fuhrman grade and poor survival. Depletion of ciRS-7 significantly inhibited RCC cell proliferation, invasion, tumor growth and metastasis in vivo, while overexpression of ciRS-7 had the opposite effect. Mechanistically, ciRS-7 acts as a "ceRNA" for miR-139-3p to prevent TAGLN degradation and promoting RCC progression and metastasis via the PI3K/AKT signaling pathway. In addition, miR-139-3p mimics or inhibitor could reverse the altered malignant tumor behavior caused by ciRS-7 overexpression or silencing. Furthermore, the PBAE/siciRS-7 nanocomplexes could significantly inhibit RCC tumor progression and metastasis in vivo. ciRS-7 acts as a tumor promoter by regulating the miR-139-3p/TAGLN axis and activating the PI3K/AKT signaling pathway to promote RCC progression and metastasis. Drug development of PBAE/si-ciRS-7 nanocomplexes targeting ciRS-7 may represent a promising gene therapeutic strategy for RCC.

Activatable Biomineralized Nanoplatform Remodels the Intracellular Environment of Multidrug-Resistant Tumors for Enhanced Ferroptosis/Apoptosis Therapy.

Ferroptosis is a new form of regulated cell death with significant therapeutic prospect, but its application against drug-resistant tumor cells is challenging due to their ability to effuse antitumor agents via p-glycoprotein (P-gp) and anti-lipid peroxidation alkaline intracellular environment. Herein, an amorphous calcium phosphate (ACP)-based nanoplatform is reported for the targeted combinational ferroptosis/apoptosis therapy of drug resistant tumor cells by blocking the MCT4-mediated efflux of lactic acid (LA). The nanoplatform is fabricated through the biomineralization of doxorubicin-Fe2+ (DOX-Fe2+ ) complex and MCT4-inhibiting siRNAs (siMCT4) and can release them to the tumor cytoplasm after the hydrolysis of ACP and dissociation of DOX-Fe2+ in the acidic lysosomes. siMCT4 can inhibit MCT4 expression and force the glycolysis-generated lactic acid (LA) to remain in cytoplasm for rapid acidification. The nanoplatform-induced remodeling of the tumor intracellular environment can not only interrupt the ATP supply required for P-gp-dependent DOX effusion to enhance H2 O2 production, but also increase the overall catalytic efficiency of Fe2+ for the initiation and propagation of lipid peroxidation. These features could act in concert to enhance the efficacy of the combinational ferroptosis/chemotherapy and prolong the survival of tumor-bearing mice. This study may provide new avenues for the treatment of multidrug-resistant tumors.

Comparison of cytotoxicity of Ag/ZnO and Ag@ZnO nanocomplexes to human umbilical vein endothelial cells in vitro.

Novel metal and metal oxide-based nanocomplexes are being developed due to their superior properties compared with nanoparticles (NPs) based on single composition. In this study, we synthesized Ag-coated ZnO (Ag/ZnO) and Ag-doped ZnO (Ag@ZnO) NPs. The cytotoxicity and mechanisms associated with the synthesized NPs were investigated to understand the influence of Ag positions on biocompatibility of the NPs. After exposure to human umbilical vein endothelial cells (HUVECs), Ag/ZnO, Ag@ZnO, and ZnO NPs all significantly induced cytotoxicity, but the cytotoxic effects of Ag/ZnO and Ag@ZnO NPs were more modest in comparison with ZnO NPs. At cytotoxic concentrations, all NPs significantly induced intracellular Zn ions, which suggested a role of excessive Zn ions on cytotoxicity of NPs. All types of NPs significantly induced the expression of endoplasmic reticulum (ER) stress genes including DNA damage-inducible transcript 3 (DDIT3), X-box binding protein 1 (XBP-1), and ER to nucleus signaling 1 (ERN1), but Ag/ZnO and Ag@ZnO NPs were less effective to induce DDIT3 and XBP-1 expression compared with ZnO NPs. Not surprisingly, only ZnO NPs significantly induced the expression of caspase 3. Combined, the results from this study showed that Ag/ZnO and Ag@ZnO NPs were less cytotoxic and less potent to induce ER stress gene expression compared with ZnO NPs, but there were no significant differences between Ag/ZnO and Ag@ZnO NPs. Our results may provide novel understanding about the biocompatibility of Ag-ZnO nanocomplexes.

Phenylboronic acid conjugated to doxorubicin nanocomplexes as an anti-cancer drug delivery system in hepatocellular carcinoma.

Anti-cancer strategies using nanocarrier systems have been explored in a variety of cancers; these systems can easily be incorporated into tumors via the enhanced permeability and retention (EPR) effect leading to enhanced anti-tumor activity while reducing systemic toxicity by specific tumor-targeting. The prognosis of hepatocellular carcinoma (HCC) is extremely poor when the condition is diagnosed at the unresectable stage as treatment options are limited. In order to improve the treatment of cancer and the overall anti-cancer effect, polymerized phenylboronic acid conjugated doxorubicin (pPBA-Dox) nanocomplexes were generated, and conjugated doxorubicin, which is conventionally used in HCC. The nanocomplexes exhibited enhanced anti-tumor activity via tumor-specific targeting in the subcutaneous and orthotopic HCC syngeneic mice tumor model, implying that the nanocomplexes facilitate the targeted Dox delivery to liver cancer in which the sialic acid is over-expressed. Therefore, this study provides insight into the novel targeted therapy using the nanocomplexes for the treatment of HCC.

Nanoarchitectonics: Complexes and Conjugates of Platinum Drugs with Silicon Containing Nanocarriers. An Overview.

The development in the area of novel anticancer prodrugs (conjugates and complexes) has attracted growing attention from many research groups. The dangerous side effects of currently used anticancer drugs, including cisplatin and other platinum based drugs, as well their systemic toxicity is a driving force for intensive search and presents a safer way in delivery platform of active molecules. Silicon based nanocarriers play an important role in achieving the goal of synthesis of the more effective prodrugs. It is worth to underline that silicon based platform including silica and silsesquioxane nanocarriers offers higher stability, biocompatibility of such the materials and pro-longed release of active platinum drugs. Silicon nanomaterials themselves are well-known for improving drug delivery, being themselves non-toxic, and versatile, and tailored surface chemistry. This review summarizes the current state-of-the-art within constructs of silicon-containing nano-carriers conjugated and complexed with platinum based drugs. Contrary to a number of other reviews, it stresses the role of nano-chemistry as a primary tool in the development of novel prodrugs.